key: cord-0772456-c74mt6e6 authors: Jorgensen, Sarah CJ.; Lapinsky, Stephen E. title: Tocilizumab for COVID-19 in pregnancy and lactation: a narrative review date: 2021-08-23 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2021.08.016 sha: 5e96d42c0e6cfb66d3163c21ca8c0fb660f397c2 doc_id: 772456 cord_uid: c74mt6e6 BACKGROUND: Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signaling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical COVID-19. Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. OBJECTIVES: To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab’s use in these populations with COVID-19. SOURCES: PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. US FDA and EMA guidance for the industry and regulatory approval documents were reviewed. CONTENT: Published data on tocilizumab in pregnancy includes 610 cases (n=20 with COVID-19) together with 7 mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared to the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow-up was limited. Tocilizumab appears to be compatible with breastfeeding. IMPLICATIONS: Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow-up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed. J o u r n a l P r e -p r o o f exposure in humans will be during the second and third trimesters when growth and maturation 157 occurs rather than during the early embryonic period when organogenesis occurs. 158 Developmental and reproductive studies are most informative when dosing extends beyond the 159 embryonic period. (27, 28) This is especially relevant for immune modulating antibodies like 160 tocilizumab since many components of the immune system continue to develop and mature 161 during the fetal and postnatal periods. 162 163 Cynomolgus monkeys have generally been used preferentially in non-clinical reproductive and 164 developmental toxicity studies of antibodies targeting the immune system because the immune 165 systems of the 2 species are similar. (28, 29) Furthermore maternofetal IgG transfer is 166 comparable to humans in terms of timing, with antibody transfer mainly occurring during the final 167 50 days of gestation, equivalent to the second and third trimesters in humans. (28, 29) 168 However, monkey antibody levels in offspring may be lower than in humans and, with respect to 169 tocilizumab in particular, monkey maternal IL-6 expression is more limited under normal 170 conditions.(11) Finally, tocilizumab tissue cross-reactivity is greater in humans compared to 171 cynomolgus monkeys where binding in the latter is restricted to inflammatory cells, endothelial 172 and epithelial cells. (11) 173 174 The rodent immune system, by contrast, is developmentally immature at the time of birth 175 compared to primates and certain aspects develop predominantly in the postnatal period. (30) 176 Antibodies are effectively transported in breastmilk in rodents and absorbed across the neonatal 177 gut by FcRn, meaning dosing in rodent studies should be extended into lactation to simulate 178 human exposure in the fetal period. (11, 30) Other barriers to using rodent models include the 179 inability of tocilizumab to bind to non-primate IL-6Rs and the high levels of anti-tocilizumab 180 J o u r n a l P r e -p r o o f antibodies produced by rodents which neutralize the effect of tocilizumab. (11, 30) To overcome 181 these problems an analogous rat anti-mouse IL-6R antibody (MR16-1) was developed and used 182 in pre/post-natal toxicity mouse studies. (11, 30) The affinity of MR16-1 to the mouse soluble IL-183 6R is approximately 14-fold lower than the affinity of tocilizumab for human soluble IL-R. 184 Despite this, MR16-1 can still suppress the acute phase response to IL-6 at low exposures in 185 mice. (11, 30) A limitation of this model however is that many mice develop fatal immune 186 reactions to low doses of MR16-1 and therefore outcomes are typically only evaluable with 187 much higher relative doses than used in humans. (11) group. Further, as can be seen in Table 1 , most patients were treated with tocilizumab for 208 rheumatologic diseases and interpretation of outcomes is complicated by underlying illness and 209 concomitant medications, some of which are known teratogens. In total 17 pregnant people whose outcomes were captured in the Roche Global Database 240 continued or resumed tocilizumab beyond the first trimester. (35) All gave birth to live neonates 241 and in prospective cases (n=11), the median gestational age at birth was 36 weeks + 4 days, 242 i.e. approximately half were preterm deliveries. A small number of cases in other reports 243 received tocilizumab beyond the first trimester but outcomes were generally not reported 244 separately (Table 1) . 245 246 There have been 4 reports of tocilizumab use in pregnant patients with COVID-19 (n=20) (Table 247 1). (31, 32, 36 , 41) Tocilizumab administration frequently occurred in the third trimester, many 248 patients were critically ill, and corticosteroid use was uncommon. In the largest series from 249 Spain (n=12), all pregnancies resulted in live births, but most had limited neonatal follow-up. 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